Process for the preparation of aminomethylene malonitrile



United States Patent 3,542,848 PROCESS FOR THE PREPARATION OF AMINOMETHYLENE MALONITRILE Willy Leimgruber, Montclair, and Manfred Weigele, North Caldwell, NJ., assignors to Hotfmann-La Roche Inc., Nutley, N.J., a corporation of New Jersey No Drawing. Filed Apr. 9, 1968, Ser. No. 719,834 Int. Cl. C07c 121/42 US. Cl. 260-465.4 3 Claims ABSTRACT OF THE DISCLOSURE This invention is directed to a process for the preparation of aminomethylene malonitrile from dialkyl aminoacrylonitrile including intermediates therein. Aminomethylene malonitrile is a known compound which is a valuable intermediate in the synthesis of thiamine.

BACKGROUND OF THE INVENTION The synthesis of thiamine has been described by a number of investigators such as Todd and Bergel in Journ. Chem. Soc., page 364, (1937). In these syntheses a pyrimidine ring compound, i.e., 2-methyl-4-amino-5- bromomethylpyrimidine dihydro-bromide and a thiazole ring compound, i.e., 4-methyl-5-fi-hydroxyethyl thiazide are condensed to form the thiamine ring structure. This pyrimidine compound is prepared from 2-methyl-4-amino- 4-cyanopyrimidine which is formed by the condensation of aminomethylene malonitrile with acetimino ethyl ether, as described in Chapter 16 of The Vitamins, Chemistry, Physiology, Pathology, vol. III, Sebrell and Harris, Academic Press, Inc., New York, (1954).

This procedure therefore depends on the use of the aminomethylene malonitrile which has been a difiicult material to synthesize economically. In view of this fact, it has long been desired to provide an economical means of synthesizing aminomethylene malonitrile utilizing inexpensive and readily available starting materials.

SUMMARY OF THE INVENTION In accordance with this invention, it has been found that aminomethrylene malonitrile, which has the formula:

CN H2NCH=O I can be synthesized economically from a dialkyl aminoacrylonitrile of the formula:

wherein R and R are lower alkyl.

In accordance with another embodiment of this invention, we have found that the starting material of Formula II can be easily synthesized from readily available and commercially economical materials by two methods. In the first method of producing the compound of Formula II above, an acetal compound of the formula:

3,542,848 Patented Nov. 24, 1970 ice wherein R and R are as above, is treated with a hydrogen acceptor at a temperature of at least 50 C. in the presence of a dehydrogenation catalyst.

DETAILED DESCRIPTION As used throughout the specification, the term lower alky includes both straight and branched chain alkyl groups containing from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, and the like. As used throughout the specification, the term lower alkanoyl" includes alkanoyl groups containing from 2 to 6 carbon atoms such as acetyl, propionyl, and butyryl.

The reaction of acetonitrile with the acetal of Formula III to form the compound of Formula II is carried out at a temperature of at least C. Generally, it is preferred to utilize a temperature of from C. to 250 C. in carrying out this reaction. While this reaction can be carried out at atmospheric pressure, superatmospheric pressures are utilized when higher temperatures are utilized. This reaction can be carried out without the need for utilizing any solvent. However, if desired, an inert organic solvent can be utilized. Any conventional inert organic solvent such as benzene, toluene, methylene chloride, can, if desired be utilized in carrying out this reaction.

The second method of preparing the compound of Formula II above is by treating a compound of Formula IV above with a hydrogen acceptor at a temperature of at least 50 C. in the presence of a dehydrogenation catalyst. Any conventional dehydrogenation catalyst can be utilized in carrying out this reaction. Among the preferred dehydrogenation catalysts which can be utilized in this reaction are palladium, Raney nickel and cupric chromite. In carrying out this reaction, any conventional hydrogen acceptor can be utilized. Among the preferred hydrogen acceptors is oxygen which can be supplied by carrying out the reaction in the presenc of air. Alternatively, the oxygen can be supplied in the form of bottled oxygen. Other hydrogen acceptors which can be advantageously utilized in this process are aliphatic ethers containing at least one ethylenic moiety bound to th oxygen atom and having from 3 to 15 carbon atoms such as methyl vinyl ether and cyclic ethers such as dihydropyran.

In converting the compound of Formula IV above to the compound of Formula II above, no solvent need be present. Generally, in carrying out this reaction, a temperature of at least 50 C. should be utilized with temperatures of between 80 C. to 200 C., being preferred. If high temperatures are utilized, the reaction may be carried out under superatmospheric pressure.

In accordance with this invention, the compound of Formula I above is synthesized from the compound of Formula II above by means of the following reaction scheme:

I'll N ltz \/\CN II R1 CN R3 R2 Ri Ye v 00/ R1 CN R1 CN v1 l i l, l N n, Ix Rz \/\CHO 112 n,

l/ \l R1 CN R1 ON wherein R and R are as above, R R R R and R are lower alkyl, Y is a halide ion, R is lower alkanoyl, and Z is the CH OSO ion.

The conversion of compounds of the Formula II above to compounds of the Formula V above is carried out, as in reaction step (a), by treating the compound of the Formula I above with a diloweralkyl formamide in the presence of an inorganic acid halide condensing agent. These three reactants may be used in any molar ratio in carrying out the reaction of step (a). In carrying out the reaction of step (a), temperatures of from about 10 C. to +10 C. should be utilized. Generally, it is preferred to carry out the reaction of step (a) in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized. However, the preferred solvents are the halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, etc. In carrying out this reaction, any of the lower alkyl formamides, preferably dimethyl formamide can be utilized. Among the preferred inorganic acid halide condensing agents which can be utilized in accordance with this invention are included phosphorous oxychloride, phosgene, thionyl chloride, phosphorous pentachloride, etc.

The compound of Formula V above is converted into the compound of Formula VI above, as in reaction step (b), by raising the pH of an aqueous solution containing the compound of Formula V above to a value of from 7 to 9. This is accomplished by treating the compound of Formula V above with an aqueous alkaline medium suflicient to raise the pH to a range of from 7 to 9. Any conventional inorganic base such as sodium hydroxide, potassium hydroxide, etc. can be utilized as the alkaline medium to provide a pH within the range of from about 7 to 9. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. If desired, elevated or reduced temperatures can be utilized.

4 The compound of Formula VI above is converted to the compound of Formula VII-A above, via reaction step (c by means of reacting the compound of the Formula VI above with a compound of the formula:

NH OR XI wherein R is as above.

In the reaction of step (c the two reactants may be used in any molar ratio. The reaction of step (c is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized. Among the inert organic solvents that can be utilized are included halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, etc. Generally, in carrying out this reaction, room temperature is utilized. During the reaction of step (c the temperature utilized should not be above 30 C. It is preferred to carry out this reaction at a temperature of from about 0 C. to 25 C.

The compound of Formula VH-A can be converted to the compound of Formula VIII via reaction step (d by heating the compound of Formula VIIA to a temperature of from 70 C. to C. The reaction of step (d is carried out in the presence of an inert organic solvent. Any of the solvents hereinbefore mentioned in connection with reaction step (c can be utilized in carrying out the reaction of step (d The compound of Formula VI above can be converted to the compound of Formula VII, via reaction step (c) by means of reacting the compound of the Formula VI with a compound of the formula:

This reaction is preferably carried out by suspending the two reactants in Water and allowing the reaction to proceed at room temperature. During the reaction of step (c), the temperature utilized should not exceed about 30 C. Generally, it is preferred to utilize a temperature of from 0 C. to 25 C. in this reaction.

The compound of Formula VII above can be converted to the compound of Formula VIII, as in reaction step (d) by adjusting the pH of the aqueous reaction mixture containing the compound of Formula VII to about 5.5 to 8.5 and warming the reaction mixture to a temperature of from about 60 C. to 90 C. The pH of the reaction mixture is adjusted to a range of 5.5 to 8.5 by treating the aqueous mixture with an alkali such as an alkali metal hydroxide. Among the preferred alkali are included sodium hydroxide, potassium hydroxide, etc.

The conversion of compounds of the Formula VI above to the compound of the Formula IX above is carried out,

as in reaction step (f), by treating the compound of the Formula VI above with a hydrazine of the formula:

Re NHg-N R XII wherein R and R are as above.

In carrying out the reaction of step (f) any mole ratio of the reactants can be utilized. Generally, this reaction is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized. Among the preferred solvents are included the lower alkanols, such as methanol, ethanol, etc. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. However, it is preferred to carry out this reaction at the reflux temperature of the solvent. Therefore, temperatures of from 50 C. to C. are generally utilized, depending upon the reflux temperature of the solvent.

The conversion of compounds of the Formula IX above to the compounds of the Formula X above, via reaction step (g), is carried out by treating the compound of the Formula IX above with a dilower alkyl sulfate. Generally, this reaction is carried out in the presence of an inert or ganic solvent. Any conventional inert organic solvent can be utilized in carrying out this reaction. Among the conventional inert organic solvents which can be utilized are included lower alkanols, such as methanol or ethanol. In carrying out this reaction, temperature and pressure 6 about 10% by weight or 30% by weight based upon the weight of the dimethylaminopropionitrile as indicated above. The final product obtained by vapor phase chromatography was dimethylaminoacrylonitrile. This product distilled at 115 C. at 3 mm. Hg.

are not critical and this reaction can be carried out at 5 EXAMPLE 2 room temperature and atmospheric pressure or at elevated temperatures. Generally, it is preferred to carry out this Pfepafatlon f 3'dlmethylamlnoacrylonltflle iiiiififillfiiiifififillliifiiriii fih. .0... 0f gzgg g of e n t m0 es) an m. o acetonitrie were p ace in fli g 5 2 1 393 1 g gg 2% 5n :1; l x a 1200 ml. autoclave. Air was removed from the autoclave e 6 mp o mu a a V6 W1 a my b flushin with nitro en, and after ur in char ed to conventional alkali such as an alkali metal hydroxide or psi Wgith nitrogen? The reaction g f i for an alkali metal lower alkoxide, can be utilized in carrying 36 hours at 0 Upon completion of the reaction react1013- Am11gtPePreferred a1-ka11 F Included excess acetonitrile was removed by vacuum distillation sodlum hydroxlde, Potasslum Pydroxlqe, Sodmm meth using a rotary evaporator at a vacuum of 135 mm. Hg. oxide, etc. This reaction is carried out 1n the presence of and a Waterbath temperature of 0 0 maximum The z: co umn. er scar n sma rt ract'on, t maethanol. In carrylng out th1s reactlon, temperature and terial boiling at 0 ig Hg collided. pressure are not critical and this reaction can be car- This material was 3 dimethylaminoacrylonitrfle ried out at room temperature and at atmospheric pres sure. If desired, elevated temperatures such as 80 C. EXAMPLE 3 can be utilized in carrying out this reaction- Preparation of (3,-dimethylamino2-cyano-2-propen-l The compound of Formula VIII above is converted into ylidene)-dimethYlammonium perchlorate the compound of Formula I above by treating the com- 10 I f N 1 pound of Formula VIII above, as in reaction step (e), 0 lmethy formamlde surfed at 4 with liquid ammonia. This reaction is generally carried to m 10 of PhOSPhOYQXY f f added out at a temperature of from minus 700 C. or below It is dropwlse 1n such a rate as to maintain the reactlon tempreferred to carry out this reaction at a temperature of perature below 0 resultmg seml'sPhd reactlon from minus to minus This reaction is ture was dlluted with 80 ml. of 1,2-d1chloroethane. On ried out by dissolving the compound of Formula VIII warmmgto room temperature, a clear amber solution above in liquid ammonia. After the compound of Formula was Obtamed' The cooled to T8 to T VIII is dissolved in liquid ammonia, the resulting solui f if"dlmethylammoacrylonltrlle, d ssolved tion is Slowly warmed to room temperature so as to nr 15 ml. of 1,2-d1chl oroethane were added dropwise with ducc the compound of Formula I above This Warming stirring within 15 minutes. After removal of the solvent should take place Within a period of time of at least 1n vacuo a semi-crystalline residue was obtained. The one hour. Generally it is preferred to, carry out this material was dissolved in 20 g. of rce/waterand 8.1 g. of warming Step Within a period of from 4 to 24 hours sodium perchlorate were added to th1s solution. On cool- Another means of converting the compound of Formula 0 mg 3-d1methy1ammO-2-cyan0 zpropen'l'yhdene)'dl' VIII above into the compound of the Formula I above is meztfilylammmlm Perchlorate as crystals 139- by treating the compound of the Formula VIII above 14 was obtamed' with a Spilfillated aqueous solution of ammonium hy- EXAMPLE 4 droxide. is reaction is carried out in an aqueous medium and by heating the aqueous mixture containing the 5 Preparatlon of 2'cyano'3'dlmethylammoacrolem compound of Formula VIII and ammonium hydroxide 36 1111- 5 ole) of N,N-dimethylformamide were to atemperature of from about 80 C. to 100 C. stirred at 0 and 36 ml. (0.392 mole) of phosphorus This invention will be more fully understood from the y o i were added dropwise Salt/ice h was specific examples which follow. These examples are inused in order to keep the reaction mixture at 0). To the tended to illustrate the invention and are not to be 50 stirring semi-solid, faintly colored reaction mixture was construed as limitative thereof. All temperatures are in added 300 ml. 0f 1,2-diChloroethane. Upon warmin to g degrees cenfigrade. room temperature by means of a water bath (25), 3. EXAMPLE 1 clear solution resulted which was cooled to 7 with an h 1 ice-salt bath. A solution of 30 ml. (0.293 mole) of [i-dig gg gi gfigg gfgg%ig to methylaminoacrylomtnle 1n 90 m1. of 1,2-dichloroethane was added dropwise keeping the temperature between The cata1yt1c dehydrogenation of d1methylam1nopro- 4 to 7. The addition required about 1 hour. The piomtrlle was carried out under the following conditions: cooling bath was removed and the clear amber reaction Reaction Reaction Hydrogen acceptor Catalyst temperature time, hours An 10% Raney nickel Reflux, 115 O 021,6 Air 30% CuCrzO; 3-24 CH2=CHO CHzCHz Palladium on carbon (10%) 50 C 24 Dihydropyran d0 Reflux, 80 C ca. 24 Do do Reflux 40 mixture allowed to come to room temperature. The reaction mixture was transferred to a 2 liter, round bottomed flask and the solvent removed in vacuo leaving a semisolid orange colored residue. A 100 g. of ice was added to the residue which gradually dissolved with evolution of heat. The solution was transferred to a beaker and the pH adjusted to 8.4 by adding carefully 2 N sodium hydroxide (815 ml. were required) to the stirred solution atmosphere. The catalyst was present in an amount of at 15-20". The resulting solution was extracted with ethyl acetate in a liquid-liquid extractor overnight. The ethyl acetate extract Was cooled, the crystals which had separated were filtered off, washed with cold ethyl acetate and dried in vacuo, affording crude 2-cyano-3-dimethylaminoacrolein, as deep yellow prisms, M.P. 143-l44. This material was dissolved in 500 ml. of hot water, treated with 2 g. of norite, the solvent removed in vacuo and the residue crystallized from absolute ethanol, producing the pure product in the form of light yellow prisms, M.P. 143-l44.

EXAMPLE Preparation of 2-cyano3-dimethylaminoacrolein Into a 250 ml. 3-neck-round-bottom flask were placed 7.3 g. (0.1 m.) of dimethylformamide and 150 ml. dichloromethane. The stirred solution was cooled in ice/ Water and phosgene was bubbled through for 30 minutes. A white solid formed. The solvent was removed in vacuo. The remaining solid was suspended in 120 ml. dichloromethane. The stirred suspension was cooled in an ice/ salt bath to C. A solution of 9.6 g. (0.1 m.) 3-dimethylaminoacrylonitrile in 40 ml. of dichloromethane was added dropwise, maintaining the temperature below 0 C. After completed addition a clear yellow solution resulted. The solution was evaporated in vacuo to dryness. The solid residue was dissolved in ml. of water. The aqueous solution was cooled to 0 C. and adjusted to pH 8.5 with 5 N sodium hydroxide solution. The alkaline solution was allowed to stand at room temperature for 4 hours, during which time a crystalline solid precipitated. The whole mixture was extracted with 5 x 100 ml. of dichloromethane. The combined organic extracts were dried over magnesium sulfate and evaporated to dryness in vacuo. The crystalline residue consisted of 2-cyano-3- dimethylaminoacrolein, M.P. 140-141. After recrystallization from ethanol, the melting point was l42l43.5.

EXAMPLE 6 Preparation of dimethylaminomethylenemalononitrile To a mixture of 10 g. of 2-cyano-3-dimethylaminoacrolein and 100 ml. of ethylene chloride was added in small portions with stirring 9 g. of O-acetylhydroxylamine hydrochloride. The mixture was stirred at room temperature for minutes and then heated at reflux temperature for 1 hour. On cooling, dimethylaminomethylenemalononitrile crystallized from the reaction solution, and was collected by filtration (M.P. 8182).

EXAMPLE 7 Preparation of N-(3-dimethylamino-2-cyano-2-propene-l ylidene)-N,N-dimethylhydrazine hydrochloride A solution f0 12.4 g. of 2-cyano-3-dimethylaminoacrolein and 9.6 g. of 1,1-dimethylhydrazine hydrochloride in ml. of methanol was heated to reflux temperature for 90 minutes. On cooling the reaction mixture a first crop of N-(3-dimethylamino-Z-cyano-Z-propene-1- ylidene)-N',N-dimethylhydrazine hydrochloride (M.P. 173) precipitated in crystalline form and was filtered off. A second crop (M.P. 170-172") was obtained from the mother liquor on concentrating.

EXAMPLE 8 Preparation of N-(3-dimethylamino-2-cyano-2-pr0pene-lylidene) -N,N'-dirnethylhydrazine 5 g. of the N-(3-dimethylamino-2-cyano-2-propene-lylidene)-N',N'-dimethylhydrazine hydrochloride was dissolved .in the minimum required amount of water. The pH was adjusted to 8 by addition of 10% sodium hydroxide solution. The desired product N (3-dimethylamino-2- cyano-Z-propene-l-ylidene)-N,N'-dimethylhydrazine precipitated and was filtered off (M.P. 130134).

8 EXAMPLE 9 Preparation of N-(3-dimethylamino-2-cyano-2-propen-1- ylidene)-N,N,N'-trimethylhydrazinium methyl sulfate 3.3 g. of N-(3-dimethylamino-2-cyano-2-propen-l-ylidene)-N',N-dimethylhydrazine were dissolved in 20 ml. of absolute ethanol. The solution was heated on a steambath, and 1.9 ml. of dimethyl sulfate was added. The resulting mixture was allowed to cool to room temperature and was then refrigerated. The product N-(3-dimethylamino 2 cyano-2-propen-1-ylidene)-N',N',N'-trimethylhydraziniurn methyl sulfate was collected by filtration (M.P. 147-149).

EXAMPLE 10 Preparation of dimethylaminomethylenemalononitrile To a solution of 2.92 g. of N-(3-dimethylamino-2- cyano 2 propen-l-ylidene)-N',N',N'-trimethylhydrazinium methyl sulfate in 20 ml. of methanol was added in small portions at room temperature 540 mg. of sodium methoxide. The resulting mixture was stirred at room temperature for 30 minutes, then the solvent was evaporated under reduced pressure. The residue was dissolved in hot water. On cooling dimethylaminomethylenemalononitrile crystallized out and was collected by filtration (M.P. 81-83").

EXAMPLE 11 Preparation of dimethylaminomethylenemalononitrile To a slurry of 12.4 g. of 2-cyano-3-dimethylaminoacrolein in 50 ml. of water was added in small portions 13.6 g. of hydroxylamine-O-sulfonic acid (91% pure). The resulting clear solution was stirred for an additional 10 minutes, then cooled to 0 and adjusted to pH 6.0 by addition of approximately 26 ml. of 5 N sodium hydroxide solution. The mixture was heated for 20 minutes in a water bath at 70. A pH 3 was maintained over this period by dropwise addition of 5 N sodium hydroxide solution. After cooling to room temperature, the mixture was extracted with 3x ml. of methylene chloride. The combined extracts were washed with 50 ml. of water, dried over magnesium sulfate, filtered and evaporated to dryness under pressure. Thus, dimethylaminomethylenemalononitrile was obtained. After recrystallization from isopropanol, the material had a melting point of 93-95".

EXAMPLE 12 Preparation of dimethylaminomethylenemalononitrile from 3-dimethylaminoacrylonitrile Into a 250 ml. 3-neck-round-bottom flask are placed 7.3 g. (0.1 m.) of dimethylformamide and 150 ml. of dichloromethane. The stirred solution is cooled in ice/ water and phosgene is bubbled through for 30 minutes. A white solid forms. The solvent is removed under reduced pressure. The remaining solid is suspended in ml. of dichloromethane. The stirred suspension is cooled in an ice/salt bath to 10. A solution of 9.6 g. (0.1 m.) of 3-dimethylaminoacrylonitrile in 40 m1. of dichloromethane is added dropwise, maintaining the temperature below 0. After completed addition a clear yellow solution results. The solution is evaporated to dryness under reduced pressure. The remaining yellow solid is dissolved in 20 ml. of water. The aqueous solution is cooled to 0 and adjusted to pH 8 with 5 N sodium hydroxide (-15 ml.). The alkaline solution is allowed to stand at room temperature for 90 minutes. A crystalline solid precipitates. The slurry is diluted with 20 ml. of water, and, while stirring 12.5 g. (0.1 m.) of hydroxylamino-O-sulfonic acid (9l93% pure) is added as a solid. A clear solution results. After 10 minutes stirring at room temperature, the solution is cooled in ice/water and the pH is adjusted to 7 with 5 N sodium hydroxide (-26 ml.). The neutral solution is heated briefly to 75 (-3-4 min.).

On cooling the main fraction of dimethylaminomethylenemalononitrile precipitates in crystalline form. The aqueous mother liquor is readjusted to pH 7 and extracted 'with 3X 100 ml. of dichloromethane. The combined organic extracts are dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 50 ml. of isopropanol. The resulting solution is treated with activated charcoal and filtered hot. On concentration of the solution an additional crop of dimethylaminomethylenemalononitrile is obtained.

EXAMPLE 14 Preparation of aminomethylenemalononitrile Into a flask, cooled in a Dry Ice/acetone bath was placed 200 mg. of dimethylaminomethylenemalononitrile. 30 ml. of ammonia was condensed into the flask. The resulting solution was allowed to come slowly to room temperature and to evaporate over a period of ca. 10 hours. The dry residue was recrystallized from water. Thus, aminomethylenemalononitrile (M.P. 139-l44) was obtained.

10 What is claimed is: 1. A compound of the formula:

R; 3N W wherein R and R are lower alkyl, and R is lower alkanoyl and -SO H. 2. A compound in accordance with claim 1, wherein R is acetyl and R and R are methyl.

3. A compound of claim 1, wherein R is SO H and R and R are methyl.

References Cited UNITED STATES PATENTS 3,466,316 9/ 1969 Payne IL, et a1. 260465.4

JOSEPH P. BRUST, Primary Examiner US. Cl. X.R. 

